We discovered a rare phenomenon wherein a thieno-pyrrole fused BODIPY dye (SBDPiR690) generates singlet oxygen without heavy halogen atom substituents. SBDPiR690 generates both singlet oxygen and fluorescence. To our knowledge, this is the first example of such a finding. To establish a structure-photophysical property relationship, we prepared SBDPiR analogs with electron-withdrawing groups at the para-position of the phenyl groups. The electron-withdrawing groups increased the HOMO-LUMO energy gap and singlet oxygen generation. Among the analogs, SBDPiR688, a CF3 analog, had an excellent dual functionality of brightness (82290 m(-1) cm(-1) ) and phototoxic power (99170 m(-1) cm(-1) ) comparable to those of Pc 4, due to a high extinction coefficient (211 000 m(-1) cm(-1) ) and balanced decay (Φflu =0.39 and ΦΔ =0.47). The dual functionality of the lead compound SBDPiR690 was successfully applied to preclinical optical imaging and for PDT to effectively control a subcutaneous tumor.
Mitochondria-specific photosensitizers were designed by taking advantage of the preferential localization of delocalized lipophilic cations (DLCs) in mitochondria. Three conjugates, CMP-Rh, CMP-tPP, and CMP-(tPP)2, were successfully synthesized by linking the hydroxy core modified porphyrins (CMP-OH and CMP-(OH)2) to either rhodamine B (Rh B) or one or two triphenyl phosphine (tPP) cations respectively via a saturated hydrocarbon linker. Their ability for delivering photosensitizers to mitochondria was evaluated using dual staining fluorescence microscopy and staining pattern was compared with a mitochondrial specific probe. Fluorescence imaging study suggested that CMP-Rh specifically localized in mitochondria. On the other hand, CMP-tPP and CMP-(tPP)2 showed less significant mitochondrial localization. The conjugation of CMP to Rh and tPP did greatly improve intracellular uptake and in vitro photodynamic activity compared to CMP-OH. In addition, to evaluate the efficiency of the conjugates as photosensitizers, their photophysical properties and in vitro biological activities were studied in comparison to those of CMP-OH. All conjugates were capable of generating singlet oxygen at rates comparable to CMP-OH. This improved photodynamic activity might be primarily due to an enhanced cellular uptake. Our study suggests that Rh B cationic group is better at least for CMP than tPP as a mitochondrial targeting vector.
Citation Format: Pallavi Rajaputra, Gregory Nkepang, Ryan Watley, Youngjae You. Synthesis and in vitro evaluation of lipophilic cation conjugated photosensitizers for targeting mitochondria. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1603. doi:10.1158/1538-7445.AM2013-1603
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